Restenosis, or recurrent lumenal narrowing, is a significant clinical problem that is especially enhanced in diabetes. With the advent of sirolimus-coated stents, the risk of restenosis after angioplasty has been strikingly reduced. Recent studies suggest the potentially powerful impact of combination therapy, such as with glycoprotein IIb/IIIa inhibitors. Therefore, it is critical to fully dissect the molecular mechanisms underlying aberrant neointimal expansion after angioplasty, as identification of new and powerful adjunctive therapies will accelerate effective therapeutic intervention strategies, particularly in diabetic subjects. Our laboratory has focused on the role of the immediate early gene, early growth response-1 (egr-1) and its key upstream regulator, PKCb, in the response to acute arterial injury. Recent observations underscored the concept that upregulation of egr-1 is linked to chronic vascular/inflammatory stress, as transcripts for egr-1 are strikingly upregulated in human and murine atherosclerotic lesions compared to adjacent non-atheromatous plaque, and after denuding arterial injury in rodents. In the vessel wall subjected to acute denuding injury in wild-type C57BL/6 mice, egr-1 is expressed rapidly after injury, particularly in smooth muscle cells (SMC) and endothelial cells (EC); in hypercholesterolemic apolipoprotein E (apo E) null (0) mice, egr-1 is also upregulated in mononuclear phagocytes (MP) infiltrating the acutely injured vessel. Our studies support a role for egr-1 and its upstream regulator, PKCBetaII in processes linked to neointimal expansion after arterial injury; mice genetically deficient in egr-1 or PKCbeta display significantly decreased neointimal expansion after femoral artery denudation injury. These considerations lead us to hypothesize that acute arterial injury results in rapid activation of PKCbetaII, thereby driving upregulation of egr-1; mechanisms linked importantly to EC, SMC, and MP activation, and modulation of neointimal expansion. We propose to dissect the mechanisms by which the PKCbetaII/egr-1 axis contributes to restenosis in vivo. To test these concepts, we will generate and characterize transgenic mice expressing functionally deficient (dominant negative, DN PKCbetaII) under the control of promoters to direct expression to EC, SMC and MP. The impact of acute denuding arterial injury in euglycemic and diabetic mice, and littermate controls will be studied. If successful, these studies will elucidate the precise cell-specific and signaling pathways by which the PKCbeta/egr-1 axis modulates the response to arterial injury and identify if these pathways are logical targets for therapeutic intervention in arterial injury.